Parathyroid hormone (PTH) has a complex and only partially understood action on bone, which mainly targets the osteoblast lineage. Many of the actions of PTH on bone are mediated by the PTH/PTHrP receptor (PPR). The proposed study aims to investigate the regulation of osteoblasts commitment, proliferation, differentiation and death by the PPR, as well as regulation of osteoclastogenesis and hematopoiesis by cells at different stages of maturation in the osteoblast lineage. In order to study these questions, cells from transgenic mice in which a constitutively active form of the PPR is expressed in the osteoblast lineage will be isolated and characterized. These mutant mice have a striking phenotype, with enormous increases in bone, osteoblasts, stromal cells and osteoclasts. This project will use an in vitro system to understand what these cells are shown to do in vivo. By studying the behavior of these cells, this project aims to define the cellular and molecular mechanisms that mediate the role of the PPR in osteoblasts. In addition, an improved understanding of the effects of PTH may provide the basis for advances in the treatment of common forms of metabolic bone disease, such as osteoporosis. The candidate states that the research project and the didactic activities proposed will help her acquire the expertise necessary to pursue a career focused on laboratory-based research of clinical relevance. Through analysis of the data obtained, discussion with her mentors and formal didactic training, she will be able to expand her knowledge of molecular genetics and development and become experienced in the field of cell biology, cell-cell interaction and signaling. Support from a KO8 award will assist in the completion of thi s proposal, and help the applicant to set out independently as an investigator, clinician and teacher in the field of PTH action and bone and mineral metabolism.